Lipid transport in blood Flashcards
overview process of fuel storage (basic)
- energy providing foods are consumed in greater quantities than needed at the time
- excess energy is stored
- CHO stored as glycogen, but store limited as liver glycogen dissapears overnight
- long term fuel store is lipid as TAG
- lipid storage is not limited = we get fat
what fuel store is limited
CHO as glycogen
what fuel store isnt limited
lipid as TAG
what is TAG
triacylglycerol
- glycerol phosphate
- 3 x fatty acids
where does TAG synthesis occur
in nearly all cells
but mostly in the liver, SI and adipose
what is glycerol phosphate
active form of glycerol and comes from glycolysis.
the phosphate group leaves once TAG is formed
state of TAG
completely hydrophobic and therefore will NOT circulate
how are TAGs made hydrophillic
addition of apoproteins and other lipids such as plp c and VLDL
plp c
phospholipid cholesterol
VLDL
very low density lipoprotein
lipoprotein structure
outer shell:
- singles layer of phospholipids, cholesterol and apoproteins
inner shell:
- TAG and cholesterol esters
what are the hydrophilic parts of lipoprotein
phospholipids
cholestorol
apoproteins
what are the hydrophobic parts of lipoprotein
TAG
cholesterol esters
state of phospholipids
hydrophilic, charged and polar
state of cholesterol
hydrophillic and polar
NOT charged
purpose of lipoprotein
allows lipid, which is insoluble in water, to be transported as a lipoprotein complex
role of apoproteins
- don’t function on their own
- structural role as they are onthe outside of lipoprptein bc hydrophillic
- recognised by receptors on cell surfaces
- activate certain enzymes in lipid metabolism
- important for transport and storage
classes of lipoproteins
chylomicrons
VLDL
LDL
HDL
how do classes of lipoproteins vary
more fat = lower density
chylomicrons
- largest and lowest density lipoprotein
- carry mainly TAG
VLDL
- very low density lipoprotein
- carries mainly endogenous fat/TAG
LDL
- low density lipoprotein
- carries mainly cholesterol to the tissue
- BAD CHOLESTEROL
HDL
- high density lipoprotien
- carries mainly cholesterol, from the tissue to the liver
- cholesterol is taken to liver for excretion
- GOOD CHOLESTEROL
what apoproteins are found on chylomicrons
apo B48
found in the intestine; fat that we eat
48 AA
what apoproteins are found on VLDL
apo B-100
100 AA
what apoproteins are found on LDL
apo B-100
100 AA
B-100
- apoprotein found on VLDL and LDL
- important for receptor recognition
- 100 AA
B-48
- apoprotein found on chylomicrons
- structural role
- 48 AA
apo-E
- apoprotein on chylomicron remnants
- important for receptor recognition
- or from HDL
apo C-11
activates LPL
- on chylomicrons
apo A-1
activates LCAT
- on HDL
How do apoproteins work as destination-targeting signals
- bind to specific receptors on the surface of cells
- binding leads to uptake of the lipoprotein bound to apo
- uptake is receptor-mediated endocytosis
= individual lipoproteins are taken up only by designated cells for specificty
what is the uptake method for lipoproteins in to cells
receptor-mediated endocytosis
LPL
lipoprotein lipase
apoproteins that activate enzymes
apo C-11 on chylomicrons activates LPL
= removes fatty acids from TAG
apo A-1 on HDL activates LCAT
= forms cholesterol in peripheral cells and phospholipd on HDL itself, and carries as ester to the liver
current average fat intakes
~80g per day
needs to be reduced by 30%
what activates LPL
- apo C-11
- insulin in absorptive state
Transport of lipid from the gut: exogenous fat
- fat eaten
- TAG from SI joins with apo-E and apo C-11 from HDL in cirucaltion to form chylomicron for cirucaltion
- LPL on capillary lining is activated by apo C-11 and insulin in absorptive state, and hydrolyses TAG
- TAG cannot move across membrane, but FA can
- FA cross to adipose where re-esterified using GP from glycolysis
- glycerol from TAG is inactive, and goes to liver where glyerol kinase activates it
- of the remaining chylomicron:
- apo C-11 returns to HDL
- apo E binds to recepto on liver causes chylomicron remnant to be internalised and reused
Transport of lipid from the gut: endogenous fat
similar to the process of exogenous liver, but starts from VLDL in the liver
- VLDL has b-100, but also picks up C-11 and E from HDL
- LPL on capillary lining is activated by apo C-11 and hydrolyses TAG
- TAG cannot move across membrane, but FA can
- FA cross to adipose where re-esterified using GP from glycolysis
- glycerol from TAG is inactive, and goes to liver where glyerol kinase activates it
- of the remaining VLDL is becomes IDL, and apo E and C-11 return to HDL
- IDL is now LDL with just B-100 apoprotein, consisting of mostly cholesterol
- 50% of LDL will go to the liver via B100 receptor
- 50% of LDL will go to periphery by B100 receptor
what does defective b100 receptor cause
high blood cholesterol
cholesterol synthesis
we do not need cholesterol from the diet becuase we can biosynthesis it
- if diet provides cholesterol, biosynthesis is reduced and number of b100 receptors on cell surface
control of cholesterol synthesis
- nucleus makes LDL receptors
- B-100 on LDL binds to receptor and whole of LDL is internalised
- lysosome forms and cholesterol is released along with proteins from LDL
- cholesterol release effects the nucles to stop synthesis of enzymes used to synthesis cholesterol
= balance between diet and biosynthesis - vegans rely on biosynthesis
who relies on cholesterol biosynthesis
vegans
LDL receptors
- very important
- recognises B-100 on LDL
- remove LDL and hence cholesterol from circulation
= receptor mediated endocytosis
LDL receptor deficiency
= familia hypercholesterolemia
- very high blood cholesterol levels
- premature death from atherosclerosis (8yrs!!)
how is cholestoerl synthesised (biochem prcess)
- acetyl CoA + acetoacetyl CoA -> HMG-CoA
- HMG-CoA -> mevalonate = rate limiting step
needs HMG-CoA reductase - mevaolonate -> cholestorel
what is the rate limiting step of cholesterol synthesis
- HMG-CoA -> mevalonate = rate limiting step
needs HMG-CoA reductase
enzyme needed for cholesterol synthesis
HMG-CoA reductase
how is cholesterol reduced therapeutically
statins
how do statins work
statins ihibit HMG-CoA reductase, and therefore decreases cholesterol synthesis in cells
- this allows liver and periphery to take up more cholesterol from the circulation
- 0.5g/day is removed from circuation by liver in the form of bile salts
what does removal of cholsterol from circulation by liver from
bile salts
alternative approaches for reducing total LDL cholesterol
- inhibitors of cholesterol absorption
- bile acid sequestering agents
= prevent reabsorption from the intestine
LCAT
lecithine cholesterol acyltransferase
- transfers acyl group (FA) from lecithine and puts it on cholesterol
LCAT AKA PCAT
lecithine = phosphatidylcholine
descirbe HDL
- high density lipoprotein
- HLD are good cholesterol
- made in SI and liver
- flat and hollow inside
- comes with Apo- A1
role of HDL in cholesterol transport
- HDL goes to peripheral cells to remove cholesterol
- LCAT is activated by apo-A1 on HDL
- LCAT removes a FA from lecithine to bind to cholesterol and transport from periphery to HDL
- cholesterol ester is formed and buried inside HDL bc neutral
- Most cholesterol ester then taken to liver for excretion
- some CE is offloaded to VLDL to allow HDL to continue removal of cholesterol
- this is becuase build up of CE in HDL inhibits LCAT
CETP
cholsterol ester transfer protein
what does CETP do
CETP allows the offloading of CE to other lipoproteins
- HDL transfers CE to LDL, IDL and VLDL
- IDL and LDL deliver contents to extrahepatic tissues but a proprtion retun to liver using LDL receptor
- transfer of CE between lipoproteins is reversible
- without CEPT, LCAT would be inhibited by CE
- inhibition of LCAT would stop efficent removal of cholsterol from circulatin
IDL
intermediate density lipoprotein
what is the recepto though which HDL delivers cholesterol directly to the liver
SR-B1
normal cholestero levels
~5
high serum cholesterol is
bad
high HDL is
good
accumulation of high cholesterol in lymphatic organs and premature CV disease =
Tangier diease
what is Tangier disease
accumulation of high cholesterol in lymphatic organs and premature CV disease =
what causes Tangier disease
- deficiency of gene coding for ABCA-1 transferase
- ABC-1 is needed to transport cholesterol out of cells to HDL and enables macrophages to unload cholesterol
ABC-1 transferase
ATP binding casette 1
- needed to transport cholesterol out of cells to HDL and enables macrophages to unload cholesterol
- antiatherogenic
antiatherogenic
preventing or inhibiting atherogenesis or antiatherogenic effects
Apo-1 milano
mutation in Apo A1 that was recognised in a lab in Milan
- Apo A1 is needed to activate LCAT
- carriers have v low HDL so expected to have high incidence of CVD
BUT
people with Apo-1 milano have been shown to live to 100
- presumably from increased efflux of cholesterol
- possible therapeutic treatment?
varieties of hyperlipidaemias
- hypercholesterolaemia
- hypertriglycerideaemia
effected by either genetics or diet and lifestyle
examples of genetic hyperlipoproteinaemias
- defective LDL receptor
- lipoprotein lipase deficiency
- deficiency of C-11
- deficiency of apoproteins involved in remnant uptake
effects of defective LDL receptor
hypercholesterolaemia
- high LDL in blood
effects of lipoprotein lipase deficiency
high chylomicrons and VLDL
effects of C-11 deficiency
high chylomicrons and VLDL
effects of deficiency of apoproteins involved in remnant uptake
- high chylomicron and VLDL remnant
risk factors for secondary hyperlipoproteinaemias
- obesity
- T2D
- dietary cholesterol
- diestry FA (SFA)
- alcoholism
how does alcohol effect lipoprotein
- exercise and small amounts of exercise increase HDL but lots of alcohol increases LDL
What lifestyle factors increase HDL
exercise and small amounts of exercise
difference of dietary FA
- SFA vs PUFA
n-6 PUFA lower cholesterol
n-3 PUFA lower TAG
what is lipoprotein a
Lp (a) is LDL with apo-A
high levels of Lp(a)
- high concentrations in plasma are associated with increased CHD risk
- levels of Lp(a) are gentic but can be increased by transfat and decreased by oestrogen
- related to plasminogen
- Lp(a) slows the breakdown of blood clots by competeing with plasminogen
CHD
coronary heart disease
what increases Lp(a)
trans fats
what decreases Lp(a)
oestrogen
what is atherosclerosis
plaque build up
plaque is:
- complex structure involving inflammation and proliferation of smooth muscle in artery wall
- contains connective tissue and pool of holesterol rich lipid
- stars as a fatty streak from accumulation of foam cells
what are foam cells
macrophages filled with lipid, mainly cholesterol
how do foam cells effect LDL metabolism
- usually LDL will go to extrahepatic cells when cholesterol is low, and to the liver for excretionwhen cholesterol is high
but, when there’s too much LDL it becomes oxidised and is no longer recognised by normal receptor
- oxidised LDL is recognised by scavenger receptor in foam cells
- scavenger regualtors are not down regulated like normal LDL receptors
= cholesterol accumulation
what happens to stored fat
hormone sensitive lipase inside adipocyt is activated by glycogen in he fasting state, and inhibited by insulin in the fed state
fasting state:
- free FA are released into bloodstream from adipocytes
- not actually ‘free’ but they are non-esterified
NEFA transport
carried adsorbed to the surface of blood protein: serum albumin
why is serum albumin a carrier for many molecules
it has hydrophobic patches on its surface and so is the carrier for many molecules with hydrophobic sections
can the brain use FFA as energy source
no, serum bound FFA cannot cross the blood brain barrier
ketone bodies function
- act on pancrease to stimulate insulin release
- insulin limits muscle proteolysis and adipose lipolysis
= conservation of muscle tissue
ketones action during fasted state
- causes insulin producting from beta cells
- start breaking down fat which limits protein breakdown
- concervse protein, which is the only source of glucose in fasted state
- glucose is needed for brain
ketones and diabetes
action of ketones is not good for diabetics
- during starvation, ketons usually causes insulin producting from beta cells
- this cant happen in diabetics
= ketoacidoses from accumulation of ketones = medical emergency
What is the mechanism by which malonyl-CoA regulates fatty acid oxidation
inhibits fatty acid transport into mitochondria
